Is TMPO p.Lys148fs (c.444del) pathogenic?

TMPO p.Lys148fs (c.444del) is classified Uncertain significance in TMPO (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-16). Associated with Loeys-Dietz syndrome 2.

What condition is associated with TMPO p.Lys148fs (c.444del)?

TMPO p.Lys148fs (c.444del) is associated with Loeys-Dietz syndrome 2 (ClinVar).

TMPO p.Lys148fs

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.444del · VCV3638118

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

Loeys-Dietz syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.7	GERP 0.82, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: TMPO
Protein: p.Lys148fs
Coding: c.444del
MANE Select: NM_001032283
Type: Deletion
Location: chr12:98531715 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB
Residue 148: the lem domain; an α-helix; the 'nakap95-binding n' region; the 'nucleoplasmic' region

Full TMPO gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Loeys-Dietz syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

TMPO p.Lys148Arg Uncertain significance ★ ⚠ same residue
TMPO c.565+1536_565+1543del Uncertain significance ★★ same condition
TMPO c.565+1928del Uncertain significance ★★ same condition
TMPO c.565+1983del Uncertain significance ★★ same condition
TMPO c.565+2304del Uncertain significance ★★ same condition
TMPO c.565+1272del Uncertain significance ★ same condition
TMPO c.565+1350_565+1352del Uncertain significance ★ same condition
TMPO c.565+1508_565+1509del Uncertain significance ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tmpo-p-lys148fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown